CDER Report to the Nation: 2003

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Table of Contents

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2 Drug Safety and Quality

Index

• Highlights
• Types of Risks from Medicines
• Drug Safety
• Adverse Event Reporting System
• MedWatch Outreach and Reporting
• Medication Guides
• Medication Error Prevention
• Drug Shortages
• Drug Recalls
• Safety-based Drug Withdrawals
• Drug Promotion Review
• Drug Product Quality
• Drug Product Quality Science

Highlights

The practical size of premarketing clinical trials means that we cannot learn everything about the safety of a drug before we approve it. Therefore, a degree of uncertainty always exists about the risks of drugs. This uncertainty requires our continued vigilance, along with that of the industry, to collect and assess data during the post-marketing life of a drug.

We monitor the quality of marketed drugs and their promotional materials through product testing and surveillance. As Americans are increasingly receiving the benefits of important new drugs before they are available to citizens of other countries, we must be especially vigilant in our surveillance. In addition, we develop policies, guidance and standards for drug labeling, current good manufacturing practices, clinical and good laboratory practices and industry practices to demonstrate the safety and effectiveness of drugs.

Highlights of drug safety and quality activities in 2003 include:

• Processing and evaluating 370,887 reports of adverse drug events, including 29,955 submitted directly from individuals.
• Reviewing about 3,000 reports of medication errors, half of which are due to error-prone labeling.
• We held a public workshop to gather consumer and scientific input on our proposals for risk management strategies during drug development and after a drug is marketed.
• Signing a cooperative research and development agreement to develop advanced software tools for quantitative analysis of drug safety data.
• Proposing a regulation that calls for over-the-counter medicines commonly used in hospitals and all prescription medicines to have a bar code. The rule became final in 2004.
• Issuing 737 letters to help ensure that the promotion of drug products presents a fair balance of risks and benefits and isn’t false or misleading.
• Clarifying our policy on prescription drugs that are sold without a prescription and providing an incentive to have them incorporated into the U.S. drug regulatory system.
• Developing technology for the rapid identification of counterfeit drug products.
• Conducting shelf-life extensions for stockpiled drugs.

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Types of Risks from Medicines

Product quality defects. These are controlled through good manufacturing practices, monitoring and surveillance.

Known side effects. Predictable adverse events are identified in the drug's labeling. These cause the majority of injuries and deaths from using medicines. Some are avoidable, and others are unavoidable.

• Avoidable. In many cases drug therapy requires an individualized treatment plan and careful monitoring. Other avoidable side effects are known drug-drug interactions.
   
• Unavoidable. Some known side effects occur with the best medical practice even when the drug is used appropriately. Examples include nausea from antibiotics or bone marrow suppression from chemotherapy.

Medication errors. For example, the drug is administered incorrectly or the wrong drug or dose is administered.

Remaining uncertainties. These include unexpected side effects, long-term effects and unstudied uses and populations. For example, a rare event occurring in fewer than 1 in 10,000 persons won't be identified in normal premarket testing.

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Drug Safety

We evaluate the safety of drugs available to American consumers using a variety of tools and disciplines. We maintain a system of postmarketing surveillance and risk assessment programs to identify adverse events that did not appear during the drug development process. We monitor adverse events such as adverse reactions, drug-drug interactions and medication errors.

We have access to commercial databases that contain non-patient-identifiable information on the actual use of marketed prescription drugs in adults and children. This dramatically augments our ability to determine the public health significance of adverse event reports we receive.

As we discover new knowledge about a drug’s safety profile, we make risk assessments and decisions about the most appropriate way to manage any new risk or new perspective on a previously known risk. Risk management methods may include new labeling, drug names, packaging, “Dear Health Care Practitioner” letters, education or special risk communications, restricted distribution programs or product marketing termination.

Risk management public workshop, concept papers

We held a three-day public workshop to discuss risk-management activities in April 2003. Before the workshop, we issued three concept papers for discussion:

• Premarketing Risk Assessment
• Risk Management Programs
• Risk Assessment of Observational Data: Good Pharmaco­vigilance Practices

The concept papers, presentations and transcripts of the workshops served as the basis for draft guidances issued in May 2004 at http://www.fda.gov/bbs/topics/news/2004/new01059.html.

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Adverse Event Reporting System

A powerful drug safety tool is the Adverse Event Reporting System. This computerized system combines the voluntary adverse drug reaction reports from MedWatch and the required reports from manufacturers. These reports often form the basis of “signals” that there may be a potential for serious, unrecognized, drug-associated events. When a signal is detected, further testing of the hypothesis is undertaken using various epidemiological and analytic databases, studies and other instruments and resources. AERS offers paper and electronic submission options, international compatibility and pharmacovigilance screening.

Adverse event reporting

In 2003, we received 370,887 reports of suspected drug-related adverse events:

• 22,955 MedWatch reports directly from individuals.
• 144,310 manufacturer 15-day (expedited) reports.
• 58,998 serious manufacturer periodic reports.
• 144,624 nonserious manufacturer periodic reports.
• nonserious).

Report types

• Direct reports from MedWatch. An individual, usually a health care practitioner, notifies us directly of a suspected serious adverse event.
• 15-day (expedited) reports. Manufacturers report serious and unexpected adverse events to us as soon as possible but within 15 days of discovering the problem.
• Manufacturer periodic reports. These report all other adverse events, such as those less than serious or described in the labeling. These are submitted quarterly for the first three years of marketing and annually after that. Nonserious reports are displayed separately starting with 1998

Electronic submissions

AERS was designed and implemented so that the majority of the reports would be entered electronically. We are in the process of migrating the reporting format from paper to electronic. In a pilot program, we are accepting electronic individual case safety reports from six major drug firms. Electronic submissions into AERS represent 21 percent of the total expedited reports we received in 2003. We estimate the cost of receiving a report is reduced at least 30 percent per report for those submitted electronically.

AERS on Internet

You can learn more about the Adverse Event Reporting System at http://www.fda.gov/cder/aers/default.htm.

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MedWatch Outreach and Reporting

We administer the MedWatch program that helps promote the safe use of drugs by:

• Rapidly disseminating new safety information on the Internet and by providing e-mail notification to health professionals, institutions, the public and our MedWatch partners consisting of professional societies, health agencies and patient and consumer groups.
   
• Providing a mechanism for health professionals and the public to voluntarily report serious adverse events, product quality problems and medication errors for all FDA-regulated medical products. Reports can be filed by mail, fax, telephone or the Internet. Direct reports, primarily from healthcare professionals, have increased by 51 percent from 1998 to 2003.
   
• Educating health professionals and consumers about the importance of recognizing and reporting serious adverse events and product problems, including medication errors. Our education program includes Internet outreach, speeches, articles and exhibits.

Individual healthcare professional and consumer subscribers to our e-mail notification service increased to more than 40,000. We also have 170 MedWatch Partner organizations. Last year, These individuals and groups received:

• 33 safety alerts for drugs.
• 25 to 45 safety-related labeling changes for drugs each month.

MedWatch drug safety Internet resources

The latest medical product safety information can be found at http://www.fda.gov/medwatch/.

You can sign up for immediate e-mail notification of MedWatch safety information at http://www.fda.gov/medwatch/elist.htm.

Data mining

We signed a two-year data mining cooperative research and development agreement with a commercial firm to develop advanced software tools for quantitative analysis of drug safety data. Data mining for simple drug-event signal generation is one part of the potential contribution data mining and related quantitative methods can make to increase our awareness and understanding of trends and patterns in adverse drug reactions.

Drugs with special safety restrictions

Controls on 10 prescription drugs include limiting distribution to specific facilities; limiting prescription to physicians with special training or expertise; or requiring certain medical tests with their use. Consumers should not buy these drugs over the Internet. As of April 30, 2003, these drugs are:

• Alosetron
• Bosentan
• Clozapine
• Dofetilide
• Fentanyl citrate
• Isotretinoin
• Mifepristone
• Sodium oxybate
• Thalidomide
• Trovafloxacin mesylate or alatrofloxacin mesylate injection

More information is at http://www.fda.gov/oc/buyonline/consumeralert120902.html.

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Medication Guides

We may require specific written patient information for selected prescription drugs that pose a serious and significant public health concern. This information is called a Medication Guide. Medication Guides must be distributed to patients with each prescription dispensed. We require Medication Guides when the information is necessary for patients to use the product safely and effectively or to decide whether to use or to continue to use the product. Last year, we approved Medication Guides for one innovator product and generic lindane and isotretinoin products:

• Mefloquine hydrochloride (Lariam).
• Lindane Shampoo (generic product).
• Lindane Lotion (generic product).
• Isotretinoin (Claravis) and Isotretinoin (Sotret), Medication Guide previously approved for Accutane and Amnesteem.

Medication Error Prevention

Avoiding name, label, packaging confusion

We work hard to ensure the safe use of drugs we approve by weeding out brand names that look or sound like the names of existing products. We identify and avoid brand names, labels and packaging that might contribute to problems or confusion in prescribing, dispensing or administering.

We review about 250 reports of medication errors each month. About half are due to error-prone labeling such as look-alike labels, poor package design and confusing names. We provide a root cause analysis of these reports that may result in revisions to the label, labeling, and/or packaging of these products to avert further error.

Our comprehensive Web site on medication errors is at
http://www.fda.gov/cder/drug/MedErrors/default.htm.

Bar codes to be required on medicines in hospitals

In March 2003, we proposed a regulation that called for over-the-counter medicines commonly used in hospitals and all prescription medicines to have a bar code. The rule became final in February 2004.

The bar-code rule aims to protect patients from preventable medication errors by helping ensure that health professionals give patients the right drugs at the appropriate dosages and at the right time. The rule will support and encourage widespread adoption of advanced information systems that, in some hospitals, have reduced medication error rates by as much as 85 percent.

We estimate that the rule will help prevent nearly 500,000 adverse events and transfusion errors while saving $93 billion in health costs over 20 years.

DailyMed update

We are collaborating on a multi-agency effort to improve patient safety through accessible medication information. Called DailyMed and still in development, the project will enable us-through the National Library of Medicine-to provide an up-to-date electronic repository of medication labeling in a standard format. This information will be useable in computer systems that support patient safety, such as electronic prescribing and decision-support systems.

Estrogen labeling safety changes

We made safety changes to the labeling of all estrogen and estrogen with progestin products for use by postmenopausal women to incorporate new risk information and to emphasize individualized decisions that appropriately balance the benefits and the potential risks of these products. These changes, including a boxed warning, reflect our analysis of the landmark Women’s Health Initiative study, sponsored by the National Institutes of Health. The study showed that postmenopausal women taking estrogen plus progestin have an increased risk of heart attack, stroke, breast cancer and blood clots. Complete information is at http://www.fda.gov/cder/drug/infopage/estrogens_progestins/default.htm.

Drugs with special safety restrictions

Controls on 10 prescription drugs include limiting distribution to specific facilities; limiting prescription to physicians with special training or expertise; or requiring certain medical tests with their use.

Consumers should not buy these drugs over the Internet.

As of April 30, 2003, these drugs are:

• Alosetron
• Bosentan
• Clozapine
• Dofetilide
• Fentanyl citrate
• Isotretinoin
• Mifepristone
• Sodium oxybate
• Thalidomide
• Trovafloxacin mesylate or alatrofloxacin mesylate injection

More information is at http://www.fda.gov/oc/buyonline/consumeralert120902.html.

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Drug Shortages

We work to help prevent or alleviate shortages of medically necessary drug products. Drug shortages occur for a variety of reasons including manufacturing difficulties, bulk supplier problems and corporate decisions to discontinue drugs. Because drug shortages can have significant public health consequences, we work with all parties involved to make sure all medically necessary products are available within the United States.

Drug shortage program aids counterterrorism effort

Utilizing data obtained from manufacturers and distributors, our drug shortage program provides supply and production information in response to federal government requests in relation to counterterrorism efforts.

Drug shortageson the Internet

We have a Web site that lists current drug shortages, describes efforts to resolve them and explains how to report them.

• The site is at http://www.fda.gov/cder/drug/shortages.
• We have an e-mail address to provide the public a communi­cation tool for drug shortage information at DrugShortages@cder.fda.gov.

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Drug Recalls

Drug recalls in fiscal year 2003

• 254 prescription drugs
• 88 over-the-counter drugs

In some cases, a drug product must be recalled due to a problem occurring in the manufacture or distribution of the product that may present a significant risk to public health. These problems usually, but not always, occur in one or a small number of batches of the drug. The most common reasons for drug recalls include those listed in the column at the left. In other cases, a drug is determined to be unsafe for continued marketing and must be withdrawn completely.

Manufacturers or distributors usually implement voluntary recalls in order to carry out their responsibilities to protect the public health when they need to remove a marketed drug product that presents a risk of injury to consumers or to correct a defective drug product. A voluntary recall of a drug product is more efficient and effective in assuring timely consumer protection than an FDA-initiated court action or seizure of the product.

How we coordinate drug recalls

We coordinate drug recall information, assist manufacturers or distributors in developing recall plans and prepare health hazard evaluations to determine the risk posed to the public by products being recalled.

We classify recall actions in accordance to the level of risk. We participate in determining recall strategies based upon the health hazard posed by the product and other factors including the extent of distribution of the product to be recalled.

We determine the need for public warnings and assist the recalling firm with public notification about the recall.

Top 10 reasons for drug recalls in fiscal year 2003:

• cGMP deviations
• Subpotency
• Stability data does not support expiration date
• Generic drug or new drug application discrepancies
• Dissolution failure
• Label mix-ups
• Content uniformity failure
• Presence of foreign substance
• pH failures
• Microbial contamination of non-sterile products

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Safety-based Drug Withdrawals

No safety-based withdrawals in 2003

In some cases, there is an intrinsic property of a drug that makes it necessary to withdraw the drug from the market for safety reasons. There were no drugs withdrawn from the U.S. market last year for safety reasons.

Record of safety-based market withdrawals

When drug withdrawals are compared based on year of approval, the recent period when we applied user-fee review goals is similar to the previous period.

Pre-PDUFA period. Between Jan. 1, 1971, and Dec. 31, 1993, we approved 477 new molecular entities, and 13 (2.7 percent) were eventually withdrawn. Nearly all the drugs we approved in this period were received before we implemented PDUFA review goals.

PDUFA period. Between Jan. 1, 1994, and April 30, 2004, we approved 303 NMEs, and 7 (2.3 percent) have been withdrawn. Nearly all drugs we approved in this period were reviewed under PDUFA goals.

Recent safety-based drug withdrawals
Drug name (year approved/year withdrawn)

• Phenylpropanolamine (-/2000) (never approved by FDA)
• Fenfluramine (1973/1997)
• Azaribine (1975/1976)
• Ticrynafen (1979/1980)
• Zomepirac (1980/1983)
• Benoxaprofen (1982/1982)
• Nomifensine (1984/1986)
• Suprofen (1985/1987)
• Terfenadine (1985/1998)
• Encainide (1986/1991)
• Astemizole (1988/1999)
• Flosequinan (1992/1993)
• Temafloxacin (1992/1992)
• Cisapride (1993/2000)
• Dexfenfluramine (1996/1997) (not an NME)
• Bromfenac (1997/1998)
• Cerivastatin (1997/2001)
• Grepafloxin (1997/1999)
• Mibefradil (1997/1998)
• Troglitazone (1997/2000)
• Rapacuronium (1999/2001)
• Alosetron* (2000/2000)
  *Returned to market in 2002 with restricted distribution.

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Drug Promotion Review

Drug promotion review statistics

We issued a total of 737 drug promotion letters last year.

• 42 regulatory action letters
• 185 launch campaigns
• 510 advisory acknowledgement or closure letters

The information about a drug available to physicians and consumers is just as important to its safe use as drug quality. We promote and protect the health of Americans by ensuring that drug advertisements and other promotional materials are truthful and balanced. We operate a comprehensive program of education, surveillance and enforcement about drug advertising and promotion.

Launches and advisories

When requested, we review advertisements and other promotional materials before drug companies launch marketing campaigns that introduce new drugs or campaigns that introduce new indications or dosages for approved drugs. In calendar year 2003, we issued 185 advisory letters to companies regarding their promotional materials for launch campaigns.

We issued 346 other advisory letters to the industry regarding proposed promotional pieces, both professional and consumer directed. In addition, we issued 159 other types of correspondence to the pharmaceutical industry, such as letters of inquiry, closure letters or acknowledgement letters.

Regulatory actions

We issued 42 regulatory action letters to companies for prescription drug promotions determined to be false, misleading, lacking in fair balance of risks and benefits or that promoted a product or indication before approval. These were either “untitled” letters for violations or “warning” letters for more serious or repeat violations. Examples of specific types of violative promotions include promotional exhibit hall displays, oral representations, Internet sites, plus traditional materials such as journal advertisements and sales brochures.

Direct-to-consumer promotion

Included in our letters were 254 regarding direct-to-consumer promotion. This compares with 188 letters in 2002. Included in last year’s letters were 47 for launch campaigns and 163 for non-launch advisories. Ten were regulatory letters.

We are working on improving our oversight of DTC advertising. Evidence from our own studies as well as those conducted by consumer groups and other entities consistently shows that DTC ads encourage some patients to seek care for undertreated conditions. This often results in a different treatment that is more appropriate for the patient than the advertised drug. But physicians and others are concerned that consumers may not always get a balanced view of the benefits and risks of a product.

DTC advertising surveys

We completed two national telephone surveys and conducted preliminary analyses. One survey of 943 consumers is a follow-up to the 1999 survey of patients’ attitudes and behaviors associated with direct-to-consumer advertisements. The other is a new survey of 500 physicians’ attitudes and behaviors associated with direct-to-consumer advertisements.

Preliminary findings of the two surveys indicate that:

• About 40 percent of patients and about 45 percent of physicians feel DTC advertising encourages information seeking about potentially serious medical conditions.
• About 80 percent of patients and 70 percent of physicians feel DTC advertising creates awareness of new treatments.
• About 42 percent of patients and 75 percent of physicians feel DTC advertising make it seem that the drug will work for everyone or make the patients think the drug works better than it does.
• About 40 percent of physicians believe that patients understand the possible risk and negative effects of drugs, compared to 80 percent who believe patients understand the benefits and positive effects.
• Slightly less than half (47%) of physicians report feeling at least a little pressure to prescribe when asked for a prescription.

More is available at http://www.fda.gov/cder/ddmac/globalsummit2003/index.htm.

DTC public meeting

To explore DTC advertising issues, we held a two-day public meeting where we presented information from our two patient and one physician surveys. We heard from researchers who have investigated the promotion of prescription drugs directed to consumers through print, broadcast and other types of media.

DTC letters

• 2003: 254
• 2002: 188
• 2001: 190
• 2000: 215
• 1999: 247
• 1998: 282
• 1997: 240

Proposed rule to revise prescription drug labeling

We continued to work on a final rule, based on comments from the public to our proposal in 2001. The main purpose of labeling is to communicate essential information about prescription drugs to health care providers.

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Drug Product Quality

We provide comprehensive regulatory coverage of the production and distribution of drug products. We manage inspection programs designed to minimize consumer exposure to defective drug products. We have two basic strategies to meet this goal:

• Evaluating the findings of inspections that examine the conditions and practices in plants where drugs are manufactured, packed, tested and stored.
• Monitoring the quality of finished drug products in distribution, through sampling and analysis.

We identify, evaluate and analyze inspection findings for trends in deficiencies. We develop guidances to assist drug manufacturers in gaining a better understanding of our regulations. We communicate the expectations of compliance through outreach programs. We review and evaluate for regulatory action all reports of FDA inspections of foreign drug manufacturing facilities. We determine which foreign manufacturers are acceptable to supply active pharmaceutical ingredients or finished drug products to the U.S. market.

Reporting systems for drug quality problems

Two important post-marketing tools help us rapidly identify significant health hazards and quality problems associated with the manufacturing and packaging of drugs:

• Drug Quality Reporting System. Through MedWatch, we receive reports of observed or suspected drug quality defects associated with marketed drugs. We evaluate and prioritize the reports to determine potential health hazards and industry trends. These reports significantly assist us in targeting potential manufacturing quality problems and identifying candidates for further sampling and analysis. We identify significant health hazards associated with drug manufacturing, packaging and labeling and initiate field inspection assignments. We review inspection reports and recommend appropriate corrective action. We maintain a central reporting system to detect problem areas and trends.
   
• Field Alert Reports. Firms are required to notify FDA promptly of possible problems that may represent safety hazards for their marketed drug products. FDA’s district offices evaluate these reports and conduct follow-up inspections. We review and evaluate the inspection findings to determine if firms are complying with reporting requirements. We review and approve enforcement recommendations for failure to meet these requirements.

Misbranded drugs, unsubstantiated claims

Mislabeled, fraudulent, hazardous products. We often encounter mislabeled and fraudulent products that make unsubstantiated claims. Consumers may use these products inappropriately or incorrectly. They may use a fraudulent product for treating a serious disease condition in place of an effective treatment or delay the use of effective treatment. For these reasons, products that are mislabeled, fraudulent or make unproven claims may pose a significant health risk.

Occasionally, fraudulent products may also contain toxic compounds that are likely to cause serious illness or injury. In addition, the marketing of products that lack required FDA approval threatens to undermine the U.S. drug development and approval process as well as the ongoing over-the-counter drug review process.

Protecting consumers from misbranded or fraudulent drugs

We protect consumers from mislabeled, fraudulent or hazardous products. We locate and identify these products for sale on the Internet as well as from traditional retail outlets, and we take steps to remove them from the market. These steps include issuing enforcement letters and pursuing enforcement actions, such as seizures of violative products and injunctions against firms or individuals.

International commerce in pharmaceuticals continues to be an important regulatory topic. We work with the FDA field force to implement legal requirements establishing which drugs may be imported by manufacturers, distributors and consumers.

We protect the public health by ensuring that imported drugs are not counterfeit and meet applicable legal requirements relating to safety and effectiveness.

Risk-based surveillance sampling of drugs

We monitor the quality of the nation’s drug supply through surveillance and sampling of foreign and domestic finished dosage forms and bulk shipments of active ingredients.

The drug products surveyed are selected according to a risk-based strategy that targets products with the greatest potential to harm the public health. FDA district offices conduct follow-up inspections to determine the cause of sample failures and to assure corrective action by the firms.

Sampling criteria

• Microbial/endotoxin concerns
• Stability concerns
• Sterility issues
• Dissolution issues
• Impurities/contaminants
• Product quality history
• Counterfeit drugs
• History of violations

Prescription drugs sold without approved applications

We identify drugs that are marketed without an approved new or generic drug application. We estimate that there are several thousand illegally marketed drug products in the United States, comprising several hundred unique molecules. We issued a draft guidance in October that describes how we intend to:

• Exercise our enforcement discretion regarding these products.
• Provide an incentive to be the first manufacturer to obtain approval for one of these drugs. After a grace period, we will consider taking enforcement action against unapproved competitors, which may result in de facto exclusivity.
• Avoid unnecessarily restricting patient access to useful medicines.
• Reiterate our risk-based criteria for enforcement action.

Manufacturing plant inspections

Preapproval inspections

During fiscal year 2003, FDA evaluated:

• 589 plants in support of new drug applications
• 864 domestic firms in support of generic drug applications

Good manufacturing practice inspections

• There were 1,512 good manufacturing practice inspections in fiscal year 2003.
• We reviewed 51 field recommendations for regulatory action and approved 34. These included 27 warning letters, four injunctions and three seizures.
• We reviewed 184 foreign establishment inspection reports, resulting in one warning letter and one import alert.

FDA field offices conduct inspections of domestic and foreign plants that manufacture, test, package and label drugs. Before a drug is approved, FDA investigators must determine if data submitted in the firm's application are authentic and if the plant is in compliance with good manufacturing practices. After a drug is approved, FDA conducts periodic inspections to make sure a firm can consistently manufacture the product with the required quality. We develop compliance programs to guide the investigators in conducting these inspections, and we identify facilities that are high priority for inspection based on their identified risk potential.

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Drug Product Quality Science

Process analytical technologies initiative

Our goal for this initiative is to facilitate the introduction of new and emerging technologies that will improve the capability and efficiency of the pharmaceutical manufacturing process while maintaining or improving product quality. Known as process analytical technologies (PAT), these are systems for continuous analysis and control of manufacturing processes based on real-time or rapid measurements during processing. They can also be non-destructive. These systems involve in-line, on-line or at-line monitoring, measuring and controlling in manufacture of drug substance and drug products.

We are using a collaborative process to develop this initiative. We are bringing together experts in the areas of analytical and physical chemistry, pharmaceutical technology, regulatory compliance, chemical engineering and international pharmaceutical manufacturing. These include experts from industry and academia along with our own and those from other FDA components.

We are encouraging the adoption of this technology in drug manufacturing because it can enhance process understanding, improve overall product quality and lead to increased efficiencies. This also addresses many of the objectives of the Pharmaceutical cGMPs for the 21st Century Initiative.

A steering committee comprised of senior FDA managers is involved in the development of a general guidance on the use of these new technologies. A special review team is now in place to evaluate process analytical technologies as the pharmaceutical industry begins implementation in existing and new manufacturing processes. On the team, our own chemistry reviewers and compliance officers will join FDA's field investigators on inspections.

By organizing public meetings and workshops, we have gathered information related to development and use of process analytical technologies and shared our own research data.

We entered into a a cooperative research and development contract with a major pharmaceutical company to develop and implement chemical imaging as a process analytical technology tool.

FDA’s effort to facilitate the introduction of new technologies to the manufacturing sector of the pharmaceutical industry now has its own Web page at http://www.fda.gov/cder/OPS/PAT.htm.

Laboratory support

We assessed several analytical technologies for characterizing active pharmaceutical ingredients and guarding against counterfeit product marketing. We applied near infrared, Raman, Isotope ratio mass spectrometry to the problem of distinguishing between production sources of active pharmaceutical ingredients and finished dosage forms. We developed methodology to better characterize nasal spray products. We evaluated a new aerodynamic particle size analyzer. We evaluated instrumentation for the determination of particle size and particle size distribution for cyclosporin drug products. We are developing physicochemical methods to assess quality changes in liposomal drug products.

Microbiology

We assess product sterility, maintenance of product safety and the microbiological controls used by firms for drug development and manufacturing. Our microbiology review assures the safety of sterile and non-sterile products through scientific evaluation and communication with the industry and assures consistency through guidance documents. We promote the development of uniform and practical test methods and criteria for our own use and through the U.S. Pharmacopoeia and the International Conference on Harmonization. We have a new program to advance rapid microbiology test methods.

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Date created: May 24, 2004